Treatment with Danazol Restores Telomere Length in Patients with Telomere Diseases

Danazol, a synthetic sex hormone with androgenic properties, preserves telomere length in patients with diseases associated with telomere dysfunction, according to the results of a phase I/II, prospective study published in the New England Journal of Medicine.

“Telomeres protect the chromosome ends from recognition as damaged or infectious DNA,” the authors, led by Danielle M. Townsley, MD, from the National Heart, Lung, and Blood Institute (NHLBI), explained. “In the telomere diseases, mutations in genes responsible for telomere maintenance and repair lead to organ dysfunction, including bone marrow failure, liver cirrhosis, and pulmonary fibrosis, as well as to an increased risk of cancer.”

Treatment with male hormones led to hematologic improvement and telomere elongation in mouse models of telomere dysfunction, leading Dr. Townsley and colleagues to assess the effects of androgen therapy on telomere preservation in patients with a variety of telomere diseases – including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and liver cirrhosis.

Twenty-seven patients (median age = 41 years; range = 17-66 years) who were consecutively enrolled at the National Institutes of Health Mark O. Hatfield Clinical Research Center between August 2011 and May 2014 were included in the study. All patients had an age-adjusted telomere length at or below the first percentile, had identified mutations in telomere maintenance and repair genes, or both, and at least one of the following:

  • Low blood count (hemoglobin level <9.5 g/dL; platelet count <30,000/mm3, or neutrophil count <1,000/mm3)
  • Pulmonary fibrosis
  • Both

Patients received danazol 800 mg daily (divided into two doses per day) for 24 months; the dose was reduced if unacceptable side effects were reported and discontinued entirely if any grade 3 or 4 adverse events (AEs) were reported.

Patients’ blood counts and liver function were evaluated at baseline and monthly after the initiation of danazol treatment.

The primary efficacy endpoint was biologic response at 24 months (defined as a reduction in the telomere length attrition rate to ≤96 bp per year), while the primary safety endpoint was toxic AEs during the 24-month treatment period. Secondary endpoints included: relapse; development of myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML); progression of pulmonary fibrosis; survival; and hematologic response (defined as an increase in hemoglobin level of ≥1.5 g/dL or no further need for transfusions or a >50% reduction in transfusions, a ≥20,000/mm3 increase in platelet count, or a ≥500/mm3 increase in neutrophil count).

Of the 27 patients enrolled, 10 had mutations in TERT, seven had mutations in TERC, three had mutations in DKC1, and one had a mutation in RTEL1. Most patients (85%) had a family history of telomere disease.

As of April 2015, 11 of the first 12 patients evaluated at 24 months had consistent telomere elongation, prompting the NHLBI to close the study early. All patients met the primary efficacy endpoint, and in the intention-to-treat analysis, the response rate was 44 percent (n=12/27; 95% CI 26-64).

Telomere elongation was noted at all time points during danazol treatment (TABLE). Patients with TERT mutation had greater telomere elongation compared with those with unidentified mutations, while those with TERC and DKC1 mutations had the smallest increase in elongation, the authors noted.

Of patients evaluable for hematologic response, 79 percent (19/24) experienced a hematologic response at three months, 81 percent (17/21) at six months, 78 percent (14/18) at 12 months, and 83 percent (10/12) at 24 months.

“To our knowledge, this is the first drug capable of preserving telomeres in humans with a genetic impairment involving telomere maintenance,” Dr. Townsley told ASH Clinical News. “These findings suggest that androgens could be studied in other disorders where telomere shortening is pathologic. For example, they could be used following chemotherapy where proliferative stress drives telomere shortening.”

Of the 13 transfusion-dependent patients at baseline, only one patient continued to require regular transfusions after danazol treatment. Patients with hemoglobin levels <9.5 g/dL at baseline saw mean increases of 3.3 g/dL (95% CI 2.1-4.4) of hemoglobin and 41,300/mm3 in their (95% CI 25,320-57,280) absolute reticulocyte count. Neutrophil counts increased by a mean of 300/mm3 (95% CI 124-476) and platelet counts increased by 14,250/mm3 (95% CI 4,880-23,620).

The most common treatment-related AEs included increased liver enzyme levels (41%), muscle cramps (33%), edema (26%), and lipid abnormalities (26%). One patient died of an acute exacerbation of pulmonary failure associated with viral pneumonia.

Three patients experienced disease progression while receiving danazol. Marrow cytogenetic abnormalities appeared in two patients, without morphologic evidence of MDS. “Lower doses of danazol or other hormone formulations are likely to have better side effect profiles,” the authors wrote.

The small patient population and mutations not always being identified in patients are limitations of this study. The researchers also suggested that a longer observation period prior to the start of danazol treatment could have provided a better baseline to assess treatment effects.

“Patients now have more options other than just transplant, and danazol may ameliorate failure of other organs, as it appeared to stabilize liver and lung disease,” Dr. Townsley said. “To adequately assess this theory, we need follow-up studies powered to investigate these endpoints.”


Reference

Townsley DM, Dumitrui B, Liu D, et al. Danazol treatment for telomere diseases. N Engl J Med. 2016;374;1922-32.

TABLE. Change in Telomere Length During Study Course
Time after Treatment Initiation Number of Patients Mean Change in Telomere Length (bp) Patients with Increase in Telomere Length
Patients Receiving Danazol
0-6 months 21 0.175

(95% CI 0.079-0.271; p=0.001)

n=16 76%

(95% CI 56-96)

0-12 months 18 0.360

(95% CI 0.209-0.512; p<0.001)

n=16 89%

(95% CI 73-100)

0-24 months 12 0.386

(95% CI 0.178-0.593; p=0.002)

n=11 92%
(95% CI 73-100)
Patients Not Receiving Danazol
24-30 months 6 -0.135 n=1 17%
24-36 months 5 -0.333 n=1 20%

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